Combination of an adenosine A2a receptor antagonist and an antidepressant or anxiolytic

ABSTRACT

This invention relates to a method of treating depression and anxiety-related disorders comprising administering to a mammal in need of such treatment an effective amount of a combination of an adenosine A 2A  antagonist and an antidepressant or an anxiolytic; another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a combination of an adenosine A 2A  antagonist and an antidepressant or anxiolytic in a pharmaceutically acceptable carrier.

CROSS REFERENCE TO RELATED APLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication 60/318,696, filed Sep. 13, 2001.

BACKGROUND

[0002] The present invention relates to a combination of an adenosineA_(2a) receptor antagonist with an antidepressant or an anxiolytic forthe treatment of depression or anxiety-related disorders. The inventionalso relates to pharmaceutical compositions comprising saidcombinations.

[0003] Adenosine is known to be an endogenous modulator of a number ofphysiological functions. At the cardiovascular system level, adenosineis a strong vasodilator and a cardiac depressor. On the central nervoussystem, adenosine induces sedative, anxiolytic and antiepilepticeffects. On the respiratory system, adenosine inducesbronchoconstriction. At the kidney level, it exerts a biphasic action,inducing vasoconstriction at low concentrations and vasodilation at highdoses. Adenosine acts as a lipolysis inhibitor on fat cells and as anantiaggregant on platelets.

[0004] Adenosine action is mediated by the interaction with differentmembrane specific receptors which belong to the family of receptorscoupled with G proteins. Biochemical and pharmacological studies,together with advances in molecular biology, have allowed theidentification of at least four subtypes of adenosine receptors: A₁,A_(2a), A_(2b) and A₃. Agonist activation of A₁ and A₃ receptors isassociated with inhibiting the activity of the enzyme adenylate cyclase,whereas activation of A_(2a) and A_(2b) receptors is associated withstimulating the activity of the same enzyme. Analogs of adenosine ableto interact as antagonists with the A₁, A_(2a), A_(2b) and A₃ receptorshave also been identified.

[0005] Selective antagonists for the A_(2a) receptor are ofpharmacological interest because of their reduced level of side effects.In the central nervous system, A_(2a) antagonists can haveantidepressant properties and stimulate cognitive functions. Moreover,data has shown that A_(2a) receptors are present in high density in thebasal ganglia, known to be important in the control of movement andemotion. Hence, A_(2a) antagonists can improve motor impairment due toneurodegenerative diseases such as Parkinson's disease, senile dementiaas in Alzheimer's disease, and psychoses of organic origin.

SUMMARY OF THE INVENTION

[0006] This invention relates to a method of treating depression oranxiety-related disorders comprising administering to a mammal in needof such treatment an effective amount of a combination of an adenosineA_(2A) antagonist and an antidepressant or an anxiolytic. In otherwords, the invention relates to the use of a combination of an adenosineA_(2A) antagonist and an antidepressant or an anxiolytic to treatdepression or anxiety-related disorders, or to the use of a combinationof an adenosine A_(2A) antagonist and an antidepressant or an anxiolyticfor the preparation of a medicament for the treatment of depression oranxiety-related disorders

[0007] Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of a combination of anadenosine A_(2A) antagonist and an antidepressant in a pharmaceuticallyacceptable carrier, or a combination of an adenosine A_(2A) antagonistand an anxiolytic in a pharmaceutically acceptable carrier.Alternatively, a pharmaceutical composition comprising an adenosineA_(2A) antagonist and a separate pharmaceutical composition comprisingan antidepressant or an anxiolytic can also be administered,simultaneously or sequentially, wherein the adenosine A_(2A) antagonistand the antidepressant or anxiolytic are administered in amounts chosenso that the combination is effective to treat depression oranxiety-related disorders. Kits comprising separate adenosine A_(2A)antagonist and antidepressant or anxiolytic pharmaceutical compositionsin a single package are also contemplated.

DETAILED DESCRIPTION

[0008] In the present invention, it has been discovered that compoundshaving adenosine A_(2a) receptor antagonist activity, in combinationwith antidepressants or anxiolytic agents, are useful in the treatmentof depression and anxiety-related disorders. Examples of anxiety-relateddisorders include social phobias, panic attack, generalized anxietydisorder (GAD), obsessive-compulsive disorders (OCD), and post-traumaticstress disorder (PTSD). The combination of the invention is useful inthe treatment of comorbid anxiety and depression in Parkinson's disease.

[0009] Suitable adenosine A_(2a) receptor antagonists can be identifiedby the binding assay described below. Specific examples of suitableadenosine A_(2a) antagonists include the compounds disclosed in severalUS patents and US and PCT patent applications.

[0010] U.S. Ser. No. 09/865,071, filed May 24, 2001, equivalent to WO01/92264, discloses compounds having the structural formula I

[0011] or a pharmaceutically acceptable salt thereof, wherein

[0012] R is R¹-furanyl, R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide,R¹-oxazolyl, R¹⁰-phenyl, R¹-pyrrolyl or C₄-C₆ cycloalkenyl;

[0013] X is C₂-C₆ alkylene or —C(O)CH₂—;

[0014] Y is —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—,—(CH₂)₂—NH—, or

[0015] and

[0016] Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl,diphenylmethyl, R⁶—C(O)—, R⁶—SO₂—, R⁶—OC(O)—, R⁷—N(R⁸)—C(O)—,R⁷—N(R⁸)—C(S)—,

[0017] phenyl-CH(OH)—, or phenyl-C(═NOR²)—; or when Q is

[0018] Z is also phenylamino or pyridylamino; or

[0019] Z and Y together are

[0020] R¹ is 1 to 3 substituents independently selected from hydrogen,C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, and C₁-C₆ alkylsulfonyl;

[0021] R² and R³ are independently selected from the group consisting ofhydrogen and C₁-C₆ alkyl;

[0022] m and n are independently 2-3;

[0023] Q is

[0024] R⁴ is 1-2 substituents independently selected from the groupconsisting of hydrogen and C₁-C₆alkyl, or two R⁴ substituents on thesame carbon can form ═O;

[0025] R⁵ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,—CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

[0026] or adjacent R⁵ substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—,—O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to whichthey are attached;

[0027] R⁶ is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, thienyl,pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-,di-((C₁-C₆)alkyl)aminomethyl, or

[0028] R⁷ is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl;

[0029] R⁸ is hydrogen or C₁-C₆ alkyl; or R⁷ and R⁸ together are—(CH₂)_(p)-A-(CH₂)_(q), wherein p and q are independently 2 or 3 and Ais a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen to whichthey are attached;

[0030] R⁹ is 1-2 groups independently selected from hydrogen, C₁-C₆alkyl, hydroxy, C₁-C₆ alkoxy, halogen, —CF₃ and(C₁-C₆)alkoxy(C₁-C₆)alkoxy;

[0031] R¹⁰ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,—CN, —NH₂, C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃ and—S(O)₀₋₂(C₁-C₆)alkyl;

[0032] R¹¹ is H, C₁-C₆ alkyl, phenyl, benzyl, C₂-C₆ alkenyl, C₁-C₆alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;

[0033] R¹² is H or C₁-C₆ alkyl; and

[0034] R¹³ is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.

[0035] Preferred compounds of formula I are those wherein R isR¹-furanyl, R¹-thienyl, R¹-pyrrolyl or R¹⁰-phenyl, more preferablyR¹-furanyl. R¹ is preferably hydrogen or halogen. Another group ofpreferred compounds is that wherein X is alkylene, preferably ethylene.Y is preferably

[0036] wherein Q is

[0037] with Q preferably being nitrogen. Preferably, m and n are each 2,and R⁴ is H. A preferred definition for Z is R⁵-phenyl, R⁵-heteroaryl,R⁶—C(O)— or R⁶—SO₂—. R⁵ is preferably H, halogen, alkyl, alkoxy,hydroxyalkoxy or alkoxyalkoxy. R⁶ is preferably R⁵-phenyl.

[0038] Preferred specific compounds of formula I are those of theformula IA

[0039] wherein R and Z-Y are as defined in the following table: Z—Y— R

[0040] Other useful adenosine A_(2a) receptor antagonists include thosedisclosed in WO 95/01356 as compounds having the structural formula II

[0041] wherein:

[0042] A is pyrazole, imidazole or a triazole ring;

[0043] R is hydrogen; C₁-C₈ alkyl; C₃-C₇ alkenyl; C₃-C₇ alkynyl; C₃-C₇cycloalkyl; C₁-C₅ alkyl substituted with one or more halogen atoms,hydroxy groups, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl, groups of formula—NR₁R₂, —CONR₁R₂; aryl optionally substituted with halogen atoms, C₁-C₄alkoxy groups, C₁-C₄ alkyl, nitro, amino, cyano, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, carboxy, carboxyamido; C₇-C₁₀, aralkyl in which the arylmoiety can be substituted with one or more of the substituents indicatedabove for the aryl group; a group of formula —(CH₂)_(m)-Het, wherein Hetis a 5-6 membered aromatic or non aromatic heterocyclic ring containingone or more heteroatoms selected from N, O, S and m is an integer from 1to 5;

[0044] R₁, R₂ which are the same or different, are hydrogen, C₁-C₅alkyl, C₇-C₁₀ aralkyl, phenyl, or taken together with the nitrogen theyare linked to, form an azetidine ring or a 5-6 membered heterocyclicring containing one or more heteroatoms such as N, O, S and n is aninteger from 2 to 5.

[0045] Preferably, compounds of formula II are those wherein R ishydrogen, C₁-C₈ alkyl, aryl or C₇-C₁₀ aralkyl optionally substituted,preferably with halogen atoms.

[0046] U.S. Pat. No. 5,935,964 discloses useful adenosine A_(2a)receptor antagonist compounds having the structural formula III

[0047] wherein

[0048] A is pyrazole, imidazole or triazole ring;

[0049] R is

[0050] R₁ and R₂, which are the same or different, are H, OH, halogen,C₁-C₄ alkoxy, C₁-C₄ alkyl, nitro, amino, cyano, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, carboxy or carboxamido; or the OH group, together with oneof R₁ or R₂, or R₁ and R₂, can form a methylenedioxy group —O—CH₂—O—;and

[0051] n is an integer from 0-4.

[0052] Preferred compounds of formula III are those wherein A ispyrazolo[4,3-e] or 1,2,3-triazolo[5,4-e].

[0053] U.S. Pat. No. 5,565,460 discloses useful adenosine A_(2a)receptor antagonist compounds having the structural formulas IVA andIVB, wherein formula IVA is

[0054] wherein

[0055] R¹ represents hydrogen, substituted or unsubstituted lower alkyl,or substituted or unsubstituted lower alkanoyl;

[0056] R² represents hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unubstitutedcycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, or a substituted or unsubstituted heterocyclicgroup;

[0057] R³ represents a substituted or unsubstituted heterocyclic group;

[0058] X represents a single bond, O, S, S(O), S(O)₂, or NR⁴ (in whichR⁴ represents hydrogen, or substituted or unsubstituted lower alkyl; orR² and NR⁴ are combined to form a substituted or unsubstituted 4 to6-membered saturated heterocyclic group): and

[0059] A represents N or CR⁵ (in which R⁵ represents hydrogen, or asubstituted or unsubstituted lower alkyl); and

[0060] wherein formula IVB is

[0061] wherein

[0062] R⁶ represents substituted or unsubstituted aryl, or a substitutedor unsubstituted heterocyclic group;

[0063] Y represents O, S, or NR⁷ (in which R⁷ represents substituted orunsubstituted lower alkyl, substituted or unubstituted cycloalkyl, orsubstituted or unsubstituted aryl);

[0064] R⁸ represents hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, substituted or unubstituted cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, or asubstituted or unsubstituted heterocyclic group; and

[0065] B and the adjacent two carbon atoms are combined to form asubstituted or unsubstituted, partially saturated or unsaturated,monocyclic or bicyclic, carbocyclic or heterocyclic group.

[0066] U.S. Provisional Application 60/329,567 discloses usefuladenosine A_(2a) receptor antagonist compounds having the structuralformula V

[0067] or a pharmaceutically acceptable salt thereof, wherein

[0068] R is R¹-heteroaryl, R¹⁰-phenyl, C₄-C₆ cycloalkenyl, —C(═CH₂)CH₃,—C≡C—CH₃, —CH═C(CH₃)₂,

[0069] X is C₁-C₆ alkylene, —C(O)CH₂— or —C(O)N(R²)CH₂—;

[0070] Y is —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—,—(CH₂)₂₋₃—N(R²)—, R⁵-divalent heteroaryl, and

[0071] Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl, R⁵-bicyclicheteroaryl, R⁵-benzofused heteroaryl, diphenylmethyl or R⁶—C(O)—;

[0072] or when Y is

[0073] Z is also R⁶—SO₂—, R⁷—N(R⁸)—C(O)— or R⁷—N(R⁸)—C(S)—;

[0074] or when Q is

[0075]  Z is also phenylamino or pyridylamino;

[0076] or Z and Y together are

[0077] R¹ is 1 to 3 substituents independently selected from hydrogen,C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, —COOR⁷ or—C(O)NR²R³;

[0078] R² and R³ are independently selected from the group consisting ofhydrogen and C₁-C₆ alkyl;

[0079] m and n are independently 2-3;

[0080] p and q are independently 0-2;

[0081] Q and Q¹ are independently selected from the group consisting of

[0082]  provided that one of Q and Q¹ is

[0083] R⁴ is 1-2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl, R¹-aryl and R¹-heteroaryl, or two R⁴substituents on the same carbon can form ═O;

[0084] R⁵ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,—CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

[0085]  (R²O)₂—P(O)—CH₂—O— and (R²O)₂—P(O)—; or adjacent R⁵ substituentstogether are —O—CH₂—O—, —O—CH₂CH₂—O—, —O—CF₂—O— or —O—CF₂CF₂—O— and forma ring with the carbon atoms to which they are attached;

[0086] R⁶ is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, thienyl,pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-,di-((C₁-C₆)alkyl)aminomethyl, or

[0087] R⁷ is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl;

[0088] R⁸ is hydrogen or C₁-C₆ alkyl; or R⁷ and R⁸ together are—(CH₂)_(p)-A-(CH₂)_(q), wherein p and q are independently 2 or 3 and Ais a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen to whichthey are attached;

[0089] R⁹ is 1-2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, halogen,—CF₃ and (C₁-C₆)alkoxy-(C₁-C₆)alkoxy;

[0090] R¹⁰ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy,—CN, —NH₂, C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃,—S(O)₀₋₂(C₁-C₆)alkyl and —CH₂—SO₂-phenyl;

[0091] R¹¹ is H, C₁-C₆ alkyl, phenyl, benzyl, C₂-C₆ alkenyl, C₁-C₆alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;

[0092] R¹² is H or C₁-C₆ alkyl;

[0093] R¹³ is H, (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—;

[0094] R¹⁴ is H, halogen, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl orNR²R³—(C₁-C₆)alkyl; and

[0095] R¹⁵ is H, halogen, C₁-C₆ alkyl or C₁-C₆ alkoxy.

[0096] Preferred compounds of formula V are those wherein R isR¹-furanyl, R¹-thienyl, R¹-pyrrolyl, R¹-pyridyl or R¹⁰-phenyl, morepreferably R¹-furanyl or R¹⁰-phenyl. R¹ is preferably hydrogen orhalogen. R¹⁰ is preferably hydrogen, halogen, alkyl or —CF₃. Anothergroup of preferred compounds is that wherein X is alkylene, preferablyethylene. Y is preferably

[0097] wherein Q is

[0098] with Q preferably being nitrogen. Preferably, m and n are each 2,and R⁴ is H. A preferred definition for Z is R⁵-phenyl or R⁵-heteroaryl.R⁵ is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy oralkoxyalkoxy. R⁶ is preferably R⁵-phenyl.

[0099] Preferred specific compounds of formula V are those of theformula VA

[0100] wherein R and Z-Y are as defined in the following table: Z—Y— R

[0101] U.S. Provisional Application 60/334,342 discloses usefuladenosine A_(2a) receptor antagonist compounds having the structuralformula VI

[0102] or pharmaceutically acceptable salts thereof, wherein

[0103] R is R¹-furanyl, R¹-thienyl, R¹-pyridyl, R¹-oxazolyl, R¹-pyrrolylor R²-phenyl;

[0104] X is —(CH₂)_(n)—;

[0105] Y is a piperidinyl or pyrrolidinyl group fused to a monocyclic orbicyclic aryl or heteroaryl wherein X is attached to the N atom of thepiperidinyl or pyrrolidinyl group;

[0106] n is an integer from 1 to 4;

[0107] R¹ is 1-3 substituents, which may be the same or different, andare independently selected from hydrogen, C₁-C₆-alkyl, —CF₃, halogen orNO₂; and

[0108] R² is 1-3 substituents, which may be the same or different, andare independently selected from hydrogen, C₁-C₆-alkyl, —CF₃, halogen,NO₂, C₁-C₆-alkoxy, C₁-C₆-acyloxy, C₁-C₆-alkylamino, C₁-C₆-acylamino,C₁-C₆-alkylsulfonamido, C₁-C₆-alkylaminosulfonyl,C₁-C₆-dialkylaminosulfonyl, aminosulfonyl, or hydroxyl.

[0109] In a preferred embodiment of compounds of formula VI, Y is

[0110] wherein A¹ is N—X, and A² and A³ each are CR⁴R⁵, or

[0111] A¹ and A³ each are CR⁴R⁵, and A² is N—X, or

[0112] A¹ and A² each are CR⁴R⁵, and A³ is N—X;

[0113] A⁴ is CR⁴R⁵;

[0114] Z¹, Z², Z³ and Z⁴ are selected from the group consisting of N andCR³, provided that 0-2 of Z¹, Z², Z³ or Z⁴ are N and the remainder areCR³;

[0115] Z⁵ is NR⁵, O, S or CR⁴R⁵;

[0116] Z⁶ is N or CR³;

[0117] Z⁷ is N or CR³;

[0118] m is an integer from 0 to 2;

[0119] R³ is hydrogen, C₁-C₆-alkyl, CF₃, halogen, NO₂, C₁-C₆-alkoxy,C₁-C₆-acyloxy, C₁-C₆-alkylamino, C₁-C₆-acylamino,C₁-C₆-alkylsulfonamino, C₁-C₆-alkylaminosulfonyl,C₁-C₆-dialkylaminosulfonyl, aminosulfonyl, or hydroxyl;

[0120] R⁴ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, —CF₃, halogen,hydroxy, or NO₂; and

[0121] R⁵ is hydrogen or C₁-C₆ alkyl.

[0122] Preferred specific examples of compounds of formula VI includecompounds of the formula VIA

[0123] wherein Y and R are defined in the following table: Y R

[0124] U.S. Provisional Application 60/334,293 discloses usefuladenosine A_(2a) receptor antagonist compounds having the structuralformula VII

[0125] or pharmaceutically acceptable salts thereof, wherein

[0126] Q and Q¹ may be the same or different and are independentlyselected from the group consisting of

[0127]  provided that one of Q and Q¹ is

[0128] m and n are independently 1-3;

[0129] p and q are independently 0-2;

[0130] W is aryl or heteroaryl having 1-3 heteroatoms, which may be thesame or different and are independently selected from N, O or S, saidaryl or heteroaryl optionally substituted by 1-3 substituents, which maybe the same or different and are independently selected from alkyl,halo, hydroxy, hydroxyalkyl, alkoxy, —NR⁶R⁷, (C₂-C₆)alkene, or —CN;

[0131] X is H, NH₂, —N(R⁶)(CH₂)_(m)—C₆H₅, —N(R⁶)(CH₂)_(m+1)—OH,—N(CH₃)₂, or

[0132] X is R¹⁸ which is attached to —Y-Z;

[0133] Y is —N(R⁶)CH₂CH₂N(R⁷)—, —OCH₂CH₂N(R⁶)—, —O—, —S—, —CH₂S—,—(CH₂)₂₋₃—N(R⁶)—, R⁸-divalent heteroaryl,

[0134] Z is alkoxyalkyl, R⁸-phenyl, R⁸-phenyl(C₁-C₆)alkyl,R⁸-heteroaryl, R⁸-bicyclic heteroaryl; R⁸-benzofused heteroaryl,diphenylmethyl or R⁹—C(O)—; or

[0135] when Y is

[0136] Z may also be H, R⁹—SO₂—, R¹⁷—N(R¹¹)—C(O)— or R¹⁷—N(R¹¹)—C(S)—;or

[0137] when Q is

[0138] Z may also be phenylamino or pyridylamino; or

[0139] Z and Y taken together are

[0140] R is R⁴-heteroaryl, R⁵-phenyl, (C₄-C₆)cycloalkenyl, —C(═CH₂)CH₃,—C≡C—CH₃,

[0141]  —CH═C(CH₃)₂, or —CH═CH—CH₃;

[0142] R² is halo, —W—X, —NH(CH₂)_(m)—W—X, —NHCH(CH₃)—W—X, or

[0143] R² is alkyl, alkenyl or —NR¹⁸R¹⁹ which is optionally substitutedby —W—X;

[0144] R³ is H, halo, alkyl, trifluoromethyl, alkoxy, alkoxyalkyl,hydroxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino,dialkylaminoalkyl, aminoalkyl, aryl, heteroaryl, or CN;

[0145] R⁴ is 1 to 3 substituents, which may be the same or different andare independently selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, —CF₃, halogen, —NO₂, —NR¹⁵R¹⁶, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, —COOR¹⁷ or—C(O)NR⁶R⁷;

[0146] R⁵ is 1 to 5 substituents, which may be the same or different andare independently selected from the group consisting of hydrogen,halogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, —CN, —NH₂,(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃,—S(O)₀₋₂(C₁-C₆)alkyl and —CH₂—SO₂-phenyl;

[0147] R⁶ and R⁷, which may be the same or different, are independentlyselected from the group consisting of hydrogen and (C₁-C₆)alkyl;

[0148] R⁸ is 1 to 5 substituents, which may be the same or different andare independently selected from the group consisting of hydrogen,halogen, (C₁-C₆)alkyl, hydroxy, C₁-C₆ alkoxy, —CN, amino,di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂, hydroxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxyhydroxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

[0149]  —O—CH₂—P(O)(OR⁶)₂,— and —P(O)(OR⁶)₂; or

[0150] adjacent R⁸ substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—,—O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to whichthey are attached;

[0151] R⁹ is (C₁-C₆)alkyl, R⁸-phenyl, R⁸-phenyl(C₁-C₆)alkyl, thienyl,pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-,di-((C₁-C₆)alkyl)aminomethyl, or

[0152] R¹⁰ is 1-2 substituents, which may be the same or different andare independently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, R⁵-aryl and R⁴-heteroaryl, or two R¹⁰ substituents on thesame carbon can form ═O;

[0153] R¹¹ is hydrogen or (C₁-C₆)alkyl; or R¹⁷ and R¹¹ taken togetherare —(CH₂)_(p)-A-(CH₂)_(q), wherein p and q are independently 2 or 3 andA is a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen towhich they are attached;

[0154] R¹² is 1-2 substituents, which may be the same or different andare independently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halogen, and —CF₃;

[0155] R¹³ is H, (C₁-C₆)alkyl, phenyl, benzyl, (C₂-C₆)alkenyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;

[0156] R¹⁴ is H, halogen, (C₁-C₆)alkyl or (C₁-C₆)alkoxy;

[0157] R¹⁵ is H or (C₁-C₆)alkyl;

[0158] R¹⁶ is H, (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—;

[0159] R¹⁷ is (C₁-C₆)alkyl, R⁸-phenyl or R⁸-phenyl(C₁-C₆)alkyl;

[0160] R¹⁸ is a bond, —CH₂—, —CH(OH)—, —CH(CH₃)—, or —C(CH₃)₂—; and

[0161] R¹⁹ is H or lower alkyl.

[0162] U.S. Provisional Application 60/334,385 discloses usefuladenosine A_(2a) receptor antagonist compounds having the structuralformula VIII

[0163] wherein:

[0164] A is C(R¹) and B is C(R^(1a)); or A is C(R¹) and B is N; or A isN and B is C(R^(1a)); or A and B are both N;

[0165] R¹ and R^(1a) are independently selected from the groupconsisting of H, (C₁-C₆)-alkyl, halo, CN and —CF₃;

[0166] Y is —O—, —S—, —SO—, —SO₂—, R⁵-heteroaryldiyl, R⁵-arylene or

[0167] p and q are independently 2-3;

[0168] Q and Q¹ are independently selected from the group consisting of

[0169]  provided that at least one of Q and Q¹ is

[0170] n is 1, 2 or 3; and

[0171] (a) A and B are both N, and X is —C(R³)(R^(3a))—, —C(O)—, —O—,—S—, —SO—, —SO₂—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or A and Bare both N, Y is a bond and X is —C(O)—, R⁴-arylene orR⁴-heteroaryldiyl; or

[0172] (b) A is C(R¹), B is N, and X is —C(R³)(R^(3a))—, —C(O)—, —O—,—S—, —SO—, —SO₂—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or A isC(R¹), B is N, Y is a bond, and X is —C(O)— or R⁴-heteroaryldiyl; or

[0173] (c) A is C(R¹), B is C(R^(1a)), and X is —C(R³)(R^(3a))—, —C(O)—,—O—, —S—, —SO—, —SO₂—, R⁴-arylene, R⁴-heteroaryldiyl, or —N(R⁹)—,provided that when X is —N(R⁹)—, R²—Y is not aryl(C₁-C₆alkyl)arylene; orA is C(R¹), B is C(R^(1a)), Y is a bond, and X is —C(R³)(R^(3a))—,—C(O)—, —O—, —S—, —SO—, —SO₂—, R⁴-arylene, —N(R⁹)— or R⁴-heteroaryldiyl,provided that when X is —N(R⁹)— or R⁴-heteroaryldiyl, R² is not phenylor phenyl(C₁-C₆)alkyl;

[0174] or n is 2 or 3; and

[0175] (d) A is N, B is C(R^(1a)), and X is —C(R³)(R^(3a))—, —C(O)—,—O—, —S—, —SO—, —SO₂—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or A isN, B is C(R^(1a)), Y is a bond and X is —C(O)—, —N(R⁹)—, R⁴-arylene orR⁴-heteroaryldiyl;

[0176] R is R⁵⁻aryl, R⁵⁻heteroaryl, R⁶—(C₂-C₆)alkenyl orR⁶-(C₂-C₆)alkynyl;

[0177] R² is R⁵⁻aryl, R⁵⁻heteroaryl, R⁵⁻aryl(C₁-C₆)alkyl orR⁵⁻heteroaryl(C₁-C₆)alkyl; or R²—Y is selected from the group consistingof

[0178] U, V, and W are independently selected from the group consistingof N and CR¹, provided that at least one of U, V and W is CR¹;

[0179] U^(a) is —O—, —S—, —NH—, or —N(C₁-C₆ alkyl)-;

[0180] R³ and R^(3a) are independently selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl and di(C₁-C₆)alkylamino(C₁-C₆)alkyl;

[0181] R⁴ is 1-3 substituents selected from the group consisting of H,(C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo,—CF₃, and —CN;

[0182] R⁵ is 1-3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy, halo, —CF₃, —CN,—NH₂, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, amino(C₁-C₆)-alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkanoylamino, (C₁-C₆)alkanesulfonylamino, (C₁-C₆)alkylthio,(C₁-C₆)alkylthio(C₁-C₆)alkyl, R⁶-(C₂-C₆)alkenyl and R⁶-(C₂-C₆)alkynyl;

[0183] R⁶ is 1 to 3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy and halo;

[0184] R⁷ and R^(7a) are independently selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C_(1-C) ₆)alkyl, R⁸-aryland R⁸-heteroaryl, or an R⁷ and an R^(7a) substituent on the same carboncan form ═O;

[0185] R⁸ is 1 to 3 substituents independently selected from H,(C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo,—CF₃, and —CN; and

[0186] R⁹ is H, C₁-C₆ alkyl, hydroxy(C₂-C₆)alkyl,(C₁-C₆)alkoxy(C₂-C₆)alkyl, amino(C₂-C₆)alkyl,(C₁-C₆)alkylamino(C₂-C₆)alkyl and di(C₁-C₆)alkylamino(C₂-C₆)alkyl.

[0187] Preferred compounds of formula VIII are those wherein A is N orC(R¹) and B is C(R^(1a)), with compounds wherein A is N and B isC(R^(1a)) being more preferred. Another group of preferred compounds isthat wherein X is —O—, —S—, —N(R⁹)— or R⁴-arylene. Preferred definitionsfor Y are a bond or piperazinyl (i.e., a group of the formula

[0188] wherein Q and Q¹ are each nitrogen, p and q are each 2, and eachR⁷ and each R^(7a) is H). R² is preferably R⁵-aryl. R is preferablyfuryl.

[0189] Preferred specific examples of compounds of formula VIII includecompounds of the formula

[0190] WO 01/02409 discloses useful adenosine A_(2a) receptor antagonistcompounds having the structural formula IX

[0191] wherein

[0192] X is O or S;

[0193] R₁ and R₂ are independently selected from hydrogen, alkyl, aryl,hydroxy, alkoky, aryloxy, cyano, nitro, CO₂R₇, COR₇, OCOR₇, CONR₇R₈,CONR₇NR₈R₉, OCONR₇R₈, NR₇R₈, NR₇COR₈, NR₇CONR₈R₉, NR₇CO₂R₈, NR₇SO₂R₈,NR₇CONR₈NR₉R₁₀, NR₇NR₈CO₂R₉, NR₇NR₈CONR₉R₁₀, NR₇SO₂NR₈R₉, SO₂R₇,SOR₇,SR₇ and SO₂NR₇R₈, or R₁ and R₂ together form a carbonyl group (C═O), anoxime group (C═NOR₁₁), an imine group (C═NR₁₁) or a hydrazine group(C═NNR₁₁R₁₂), or R₁ and R₂ together form a 5, 6 or 7 memberedcarbocyclic or heterocyclic ring;

[0194] R₃ is alkyl or aryl;

[0195] R₄, R₅ and R₆ ate independently selected from hydrogen, alkyl,aryl, halogen, hydroxy, nitro, cyano, alkoxy, aryloxy, CO₂R₇, COR₇,OCOR₇, SO₂R₇, SOR₇, SR₇, SO₂NR₇R₈,, CONR₇R₈, CONR₇NR₈R₉, OCONR₇R₈,NR₇R₈, NR₇COR₈, NR₇CONR₈R₉, NR₇CO₂R₈, NR₇SO₂R₈, CR₇═NOR₈,NR₇CONR₈NR₉R₁₀, NR₇NR₈CO₂R₉, NR₇NR₈CONR₉R₁₀, SO₂NR₇NR₈R₉, NR₇SO₂NR₈R₉,NR₇NR₈SO₂R₉, NR₇NR₈CO₂R₉, NR₇NR₈R₉ and NR₇CSNR₈R₉, or R₅ and R₆ togetherform a 5, 6 or 7 membered carbocyclic or heterocyclic ring; and

[0196] R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are independently selected fromhydrogen, alkyl and aryl, or a pharmaceutically acceptable salt orprodrug thereof.

[0197] Agents known to be useful in the treatment of depression(“antidepressants”) which can be administered in combination with anadenosine A_(2a) receptor antagonist include: selective serotoninreuptake inhibitors such as fluoxetine, sertraline, paroxetine,citalopram, mirtazepine and fluvoxamine; selective norepinephrinereuptake inhibitors such as reboxetine, desipramine, amitriptyline,nortriptyline and imipramine; mixed serotonin/ norepinephrine reuptakeinhibitors such as venlafaxine, buproprion, nefazodone and milnacipran,and combinations thereof.

[0198] Agents known to be useful in the treatment of anxiety-relateddisorders (i.e., anxiolytics) which can be administered in combinationwith an adenosine A_(2a) receptor antagonist include alprazolam,buspirone, lorazepam, diazepam, clonazepam, doxepin, chlordiazepoxideand meprobamate, and combinations thereof.

[0199] The US patents and applications cited herein are incorporatedherein by reference. The adenosine A_(2a) receptor antagonists areprepared by known methods as described in the cited patents andapplications. The antidepressants and anxiolytics are commerciallyavailable and are described in the literature, e.g., in The Physicians'Desk Reference (Montvale: Medical Economics Co., Inc., 2001)

[0200] It is contemplated that two or more A_(2a) receptor antagonistscould be administered in combination with one or more antidepressants orone or more anxiolytics to treat depression or anxiety-relateddisorders; it is also contemplated that one or more antidepressants andone or more anxiolytics could be combined with one or more A_(2a)receptor antagonists for the treatment of depression or anxiety-relateddisorders.

[0201] The pharmacological activity of the compounds of the inventionwas determined by the following in vitro and in vivo assays to measureA_(2a) receptor activity.

[0202] Human Adenosine A_(2a) and A₁ Receptor Competition Binding AssayProtocol

[0203] Membrane sources:

[0204] A_(2a): Human A_(2a) Adenosine Receptor membranes, Catalog#RB-HA2a, Receptor Biology, Inc., Beltsville, Md. Dilute to 17 μg/100 μlin membrane dilution buffer (see below).

[0205] Assay Buffers:

[0206] Membrane dilution buffer: Dulbecco's Phosphate Buffered Saline(Gibco/BRL)+10 mM MgCl₂.

[0207] Compound Dilution Buffer: Dulbecco's Phosphate Buffered Saline(Gibco/BRL)+10 mM MgCl₂ supplemented with 1.6 mg/ml methyl cellulose and16% DMSO. Prepared fresh daily.

[0208] Ligands:

[0209] A_(2a): [3H]-SCH 58261, custom synthesis, AmershamPharmaciaBiotech, Piscataway, N.J. Stock is prepared at 1 nM in membrane dilutionbuffer. Final assay concentration is 0.5 nM.

[0210] A₁: [3H]-DPCPX, AmershamPharmacia Biotech, Piscataway, N.J. Stockis prepared at 2 nM in membrane dilution buffer. Final assayconcentration is 1 nM.

[0211] Non-specific Binding:

[0212] A_(2a): To determine non-specific binding, add 100 nM CGS 15923(RBI, Natick, Mass.). Working stock is prepared at 400 nM in compounddilution buffer.

[0213] A₁: To determine non-specific binding, add 100 μM NECA (RBI,Natick, Mass.). Working stock is prepared at 400 μM in compound dilutionbuffer.

[0214] Compound Dilution:

[0215] Prepare 1 mM stock solutions of compounds in 100% DMSO. Dilute incompound dilution buffer. Test at 10 concentrations ranging from 3 μM to30 pM. Prepare working solutions at 4×final concentration in compounddilution buffer.

[0216] Assay procedure:

[0217] Perform assays in deep well 96 well plates. Total assay volume is200 μl. Add 50 μl compound dilution buffer (total ligand binding) or 50μl CGS 15923 working solution (A_(2a) non-specific binding) or 50 μlNECA working solution (A₁ non-specific binding) or 50 μl of drug workingsolution. Add 50 μl ligand stock ([3H]-SCH 58261 for A_(2a), [3H]-DPCPXfor A₁). Add 100 μl of diluted membranes containing the appropriatereceptor. Mix. Incubate at room temperature for 90 minutes. Harvestusing a Brandel cell harvester onto Packard GF/B filter plates. Add 45μl Microscint 20 (Packard), and count using the Packard TopCountMicroscintillation Counter. Determine IC₅₀ values by fitting thedisplacement curves using an iterative curve fitting program (Excel).Determine Ki values using the Cheng-Prusoff equation.

[0218] Haloperidol-induced Catalepsy in the Rat

[0219] Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing175-200 g are used. The cataleptic state is induced by the subcutaneousadministration of the dopamine receptor antagonist haloperidol (1 mg/kg,sc), 90 min before testing the animals on the vertical grid test. Forthis test, the rats are placed on the wire mesh cover of a 25×43plexiglass cage placed at an angle of about 70 degrees with the benchtable. The rat is placed on the grid with all four legs abducted andextended (“frog posture”). The use of such an unnatural posture isessential for the specificity of this test for catalepsy. The time spanfrom placement of the paws until the first complete removal of one paw(decent latency) is measured maximally for 120 sec.

[0220] The selective A_(2A) adenosine antagonists under evaluation areadministered orally at doses ranging between 0.03 and 3 mg/kg, 1 and 4 hbefore scoring the animals.

[0221] In separate experiments, the anticataleptic effects of thereference compound, L-DOPA (25, 50 and 100 mg/kg, ip), were determined.

[0222] 6-OHDA Lesion of the Middle Forebrain Bundle in Rats

[0223] Adult male Sprague-Dowley rats (Charles River, Calco, Como,Italy), weighing 275-300 g, are used in all experiments. The rats arehoused in groups of 4 per cage, with free access to food and water,under controlled temperature and 12 hour light/dark cycle. The daybefore the surgery the rats are fasted over night with water ad libitum.

[0224] Unilateral 6-hydroxydopamine (6-OHDA) lesion of the middleforebrain bundle is performed according to the method described inUngerstedt et al, Brian Research, 24 (1970), p. 485-493, and Ungerstedt,Eur. J. Pharmacol., 5 (1968), p.107-110, with minor changes. Briefly,the animals are anaesthetized with chloral hydrate (400 mg/kg, ip) andtreated with desipramine (10 mpk, ip) 30 min prior to 6-OHDA injectionin order to block the uptake of the toxin by the noradrenergicterminals. Then, the animals are placed in a stereotaxic frame. The skinover the skull is reflected and the stereotaxic coordinates (−2.2posterior from bregma (AP), +1.5 lateral from bregma (ML), 7.8 ventralfrom dura (DV) are taken, according to the atlas of Pellegrino et al(Pellegrino L. J., Pellegrino A. S. and Cushman A. J., A StereotaxicAtlas of the Rat Brain. 1979, New York: Plenum Press). A burr hole isthen placed in the skull over the lesion site and a needle, attached toa Hamilton syringe, is lowered into the left MFB. Then 8 μg 6-OHDA-HClis dissolved in 4 μl of saline with 0.05% ascorbic acid as antioxidant,and infused at the constant flow rate of 1 μl/1 min using an infusionpump. The needle is withdrawn after additional 5 min and the surgicalwound is closed and the animals left to recover for 2 weeks.

[0225] Two weeks after the lesion the rats are administered with L-DOPA(50 mg/kg, ip) plus Benserazide (25 mg/kg, ip) and selected on the basisof the number of full contralateral turns quantified in the 2 h testingperiod by automated rotameters (priming test). Any rat not showing atleast 200 complete turns/2 h is not included in the study.

[0226] Selected rats receive the test drug 3 days after the priming test(maximal dopamine receptor supersensitivity). The new A_(2A) receptorantagonists are administered orally at dose levels ranging between 0.1and 3 mg/kg at different time points (i.e., 1, 6, 12 h) before theinjection of a subthreshold dose of L-DOPA (4 mpk, ip) plus benserazide(4 mpk, ip) and the evaluation of turning behavior.

[0227] In the binding assay, adenosine A_(2a) receptor antagonists foruse in the present invention preferably show A_(2a) Ki vaules of 0.3 to100 nM, with preferred compounds showing Ki values between 0.3 and 5.0nM.

[0228] Selectivity is determined by dividing Ki for A, receptor by Kifor A_(2a) receptor. Preferred compounds of the invention have aselectivity ranging from about 100 to about 2000.

[0229] Preferred compounds showed a 50-75% decrease in descent latencywhen tested orally at 1 mg/kg for anti-cataleptic activity in rats.

[0230] In the 6-OHDA lesion test, rats dosed orally with 1 mg/kg of thepreferred compounds performed 170-440 turns in the two-hour assayperiod.

[0231] In the haloperidol-induced catalepsy test, a combination ofsub-threshold amount of a compound of formula I and a sub-thresholdamount of L-DOPA showed a significant inhibition of the catalepsy,indicating a synergistic effect. In the 6-OHDA lesion test, test animalsadministered a combination of a compound of formula I and asub-threshold amount of L-DOPA demonstrated significantly higher(6-fold) contralateral turning.

[0232] Depression and anxiety are measure by the following tests,wherein immobility is an indication of depression.

[0233] Mouse Tail Suspension Test

[0234] The tail suspension test is based on the observation that a mousesuspended by the tail shows alternate periods of agitation andimmobility. The mouse, acoustically and visually isolated, is hung onthe hook by an adhesive tape placed 20 mm from the extremity of its tailand it is kept 150 mm away from the nearest object. The duration ofimmobility is recorded for 6 min. The sum of immobility periods(duration of immobility) is measured by an observer who was unaware ofthe drug treatments. Each mouse is used only once for each experimentalsession.

[0235] Mouse and Rat Forced Swim Test

[0236] Mouse: In the forced swimming test, mice are dropped individuallyinto glass cylinders (height: 25 cm, diameter: 10 cm) containing 10 cmwater, maintained at 25° C., and left there for 6 min. A mouse is judgedto be immobile when it floats in an upright position, and makes onlysmall movements to keep its head above water. The duration of immobilityis recorded during the last 4-min of the 6-min testing period. The sumof immobility periods (duration of immobility) is measured by anobserver who is unaware of the drug treatments. Each mouse is used onlyonce for each experimental session.

[0237] Rat: Rat is placed in a cylinder 40 cm high and 18 cm in diametercontaining 20 cm of water at 25° C. The animal is left to swim in thewater for 15 min before being removed, allowed to dry beside a heatedenclosure and returned to its home cage. Twenty-four h later, the animalis exposed again to the conditions outlined above and the totalimmobility time during a 5-min period recorded (test session).Furthermore, we also measure the active behavior of the animal as thetime spent in climbing. Drugs are given 3 times before testing: 24, 5and 1 h. In each test the measurements are always made under blindconditions.

[0238] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

[0239] For preparing suppositories, a low melting wax such as a mixtureof fatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

[0240] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection.

[0241] Liquid form preparations may also include solutions forintranasal administration.

[0242] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

[0243] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0244] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0245] Preferably the compounds are administered orally.

[0246] Preferably, when the combination of drugs is administered in asingle pharmaceutical composition, the pharmaceutical preparation is inunit dosage form. In such form, the preparation is subdivided into unitdoses containing appropriate quantities of each active component, e.g.,an amount effective to achieve the desired purpose.

[0247] The amount and frequency of administration of the compounds inthe combination of this invention will be regulated according to thejudgment of the attending clinician considering such factors as age,condition and size of the patient as well as severity of the symptomsbeing treated. Determination of the proper dosage for a particularsituation is within the skill of the art. Generally, treatment isinitiated with smaller dosages which are less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day, if desired.

[0248] The combination of drugs can be administered individually, eithersimultaneously or sequentially, in any conventional dosage form such ascapsule, tablet, powder, cachet, suspension, solution, suppository,nasal spray, etc. Different drugs can be administered in differentdosage forms. When used in combination, the dosage levels of theindividual components are preferably lower than the recommendedindividual dosages because of the advantageous effect of thecombination.

[0249] The quantity of adenosine A_(2a) receptor antagonist in a unitdose of preparation may be varied or adjusted from about 0.1 mg to 1000mg, more preferably from about 1 mg to 300 mg, according to theparticular application. A typical recommended dosage regimen for anadenosine A_(2a) receptor antagonist is oral administration of from 10mg to 2000 mg/day, preferably 10 to 1000 mg/day, in two to four divideddoses to treat depression or anxiety-related disorders.

[0250] The doses and dosage regimens of the antidepressant andanxiolytic components of the combination will be determined by theattending clinician in view of the approved doses and dosage regimenknown in the art, e.g., in the package insert or other publishedinformation, taking into consideration the age, sex and condition of thepatient and the severity of the disease.

[0251] When the adenosine A_(2a) receptor antagonist and antidepressantor anxiolytic are to be administered separately, they can be provided ina kit comprising in a single package, one container comprising anadenosine A_(2a) receptor antagonist in a pharmaceutically acceptablecarrier, and a separate container comprising an antidepressant oranxiolytic in a pharmaceutically acceptable carrier, with the adenosineA_(2a) receptor antagonist and the antidepressant or anxiolytic agentbeing present in an amount such that the combination is effective totreat depression or anxiety-related disorders. A kit is advantageous foradministering a combination when, for example, the components must beadministered at different time intervals or when they are in differentdosage forms (i.e., tablet and capsule).

[0252] The following are examples of pharmaceutical dosage formssuitable for the present invention. Those skilled in the art willrecognize that dosage forms are suitable for single actives (i.e.“Active” is an A_(2a) receptor antagonist or an antidepressant or ananxiolytic), or can contain both components (ie, “Active” comprises bothan adenosine A_(2a) receptor antagonist and an antidepressant oranxiolytic). The scope of the invention in its pharmaceuticalcomposition aspect is not to be limited by the examples provided.

Pharmaceutical Dosage Form Examples EXAMPLE A Tablets

[0253] No. Ingredients mg/tablet mg/tablet 1. Active compound 100 500 2.Lactose USP 122 113 3. Corn Starch, Food Grade, as a 30 40 10% paste inPurified Water 4. Corn Starch, Food Grade 45 40 5. Magnesium Stearate 37 Total 300 700

[0254] Method of Manufacture

[0255] Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.Granulate the mixture with Item No. 3. Mill the damp granules through acoarse screen (e.g., ¼″, 0.63 cm) if necessary. Dry the damp granules.Screen the dried granules if necessary and mix with Item No. 4 and mixfor 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B Capsules

[0256] No. Ingredient mg/capsule mg/capsule 1. Active compound 100 5002. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4. MagnesiumStearate NF 7 7 Total 253 700

[0257] Method of Manufacture

[0258] Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes.Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

[0259] While the present invention has been described in conjunctionwith the specific embodiments set forth above, many alternatives,modifications and variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

We claim:
 1. A method of treating depression or anxiety-relateddisorders comprising administering to a mammal in need of such treatmentan effective amount of a combination of an adenosine A_(2A) antagonistand an antidepressant or an anxiolytic.
 2. The method of claim 1 whereinthe adenosine A_(2a) receptor antagonist is selected from thosedescribed in formulas I, II, III, IVA, IVB, V, VI, VII, VIII and IX asdisclosed in the specification.
 3. The method of claim 1 wherein theantidepressant is selected from selective serotonin reuptake inhibitors,selective norepinephrine reuptake inhibitors, and mixedserotonin/norepinephrine reuptake inhibitors.
 4. The method of claim 3wherein the antidepressant is selected from fluoxetine, sertraline,paroxetine, citalopram, mirtazepine, fluvoxamine, reboxetine,desipramine, amitriptyline, nortriptyline, imipramine, venlafaxine,buproprion, nefazodone and milnacipran.
 5. The method of claim 1 whereinthe anxiolytic is selected from alprazolam, buspirone, lorazepam,diazepam, clonazepam, doxepin, chlordiazepoxide and meprobamate.
 6. Themethod of claim 1 wherein the adenosine A_(2a) receptor antagonist isselected from those described in formulas I, II, III, IVA, IVB, V, VI,VII, VIII and IX as disclosed in the specification; the antidepressantis selected from fluoxetine, sertraline, paroxetine, citalopram,mirtazapine, fluvoxamine, reboxetine, desipramine, amitriptyline,nortriptyline, imipramine, venlafaxine, buproprion, nefazodone andmilnacipran; and the anxiolytic is selected from alprazolam, buspirone,lorazepam, diazepam, clonazepam, doxepin, chlordiazepoxide andmeprobamate.
 7. The method of claim 6 wherein the adenosine A_(2a)receptor antagonist is represented by the structural formula I

or a pharmaceutically acceptable salt thereof, wherein R is R¹-furanyl,R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide, R¹-oxazolyl, R¹⁰-phenyl,R¹-pyrrolyl or C₄-C₆ cycloalkenyl; X is C₂-C₆ alkylene or —C(O)CH₂—; Yis —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—, —(CH₂)₂—NH—, or

and Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl,diphenylmethyl, R⁶—C(O)—, R⁶—SO₂—, R⁶—OC(O)—, R⁷—N(R⁸)—C(O)—,R⁷—N(R⁸)—C(S)—,

 phenyl-CH(OH)—, or phenyl-C(═NOR²)—; or when Q is

 Z is also phenylamino or pyridylamino; or Z and Y together are

R¹ is 1 to 3 substituents independently selected from hydrogen,C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, a C₁-C₆ alkylsulfonyl; R² and R³ areindependently selected from the group consisting of hydrogen and C₁-C₆alkyl; m and n are independently 2-3; Q is

R⁴ is 1-2 substituents independently selected from the group consistingof hydrogen and C₁-C₆alkyl, or two R⁴ substituents on the same carboncan form ═O; R⁵ is 1 to 5 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, —CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

 or adjacent R⁵ substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—,—O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to whichthey are attached; R⁶ is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl,thienyl, pyridyl, (C₃-C₆)-cycloalkyl,(C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl, or

R⁷ is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl; R⁸ is hydrogenor C₁-C₆ alkyl; or R⁷ and R⁸ together are —(CH₂)_(p)-A-(CH₂)_(q),wherein p and q are independently 2 or 3 and A is a bond, —CH₂—, —S— or—O—, and form a ring with the nitrogen to which they are attached; R⁹ is1-2 groups independently selected from hydrogen, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, halogen, —CF₃ and (C₁-C₆)alkoxy(C₁-C₆)alkoxy; R¹⁰ is 1 to5 substituents independently selected from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —CN, —NH₂,C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃ and—S(O)₀₋₂(C₁-C₆)alkyl; R¹¹ is H, C₁-C₆ alkyl, phenyl, benzyl, C₂-C₆alkenyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl; R¹² is H or C₁-C₆alkyl; and R¹³ is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.
 8. The methodof claim 7 wherein the adenosine A_(2a) receptor antagonist isrepresented by the formula

wherein R and Z-Y are as defined in the following table: Z—Y— R


9. A pharmaceutical composition comprising a therapeutically effectiveamount of a combination of an adenosine A_(2a) receptor antagonist andan antidepressant or an anxiolytic in a pharmaceutically acceptablecarrier.
 10. The composition of claim 9 wherein the adenosine A_(2a)receptor antagonist is selected from those described in formulas I, II,III, IVA, IVB, V, VI, VII, VIII and IX as disclosed in thespecification.
 11. The composition of claim 9 wherein the antidepressantis selected from selective serotonin reuptake inhibitors, selectivenorepinephrine reuptake inhibitors, and mixed serotonin/norepinephrinereuptake inhibitors.
 12. The composition of claim 11 wherein theantidepressant is selected from fluoxetine, sertraline, paroxetine,citalopram, mirtazapine, fluvoxamine, reboxetine, desipramine,amitriptyline, nortriptyline, imipramine, venlaflaxine, buproprion,nefazodone and milnacipran.
 13. The composition of claim 9 wherein theanxiolytic is selected from alprazolam, buspirone, lorazepam, diazepam,clonazepam, doxepin, chlordiazepoxide and meprobamate.
 14. Thecomposition of claim 9 wherein the adenosine A_(2a) receptor antagonistis selected from those described in formulas I, II, III, IVA, IVB, V,VI, VII, VIII and IX as disclosed in the specification; theantidepressant is selected from fluoxetine, sertraline, paroxetine,citalopram, mirtazapine, fluvoxamine, reboxetine, desipramine,amitriptyline, nortriptyline, imipramine, venlaflaxine, buproprion,nefazodone and milnacipran; and the anxiolytic is selected fromalprazolam, buspirone, lorazepam, diazepam, clonazepam, doxepin,chlordiazepoxide and meprobamate.
 15. The composition of claim 14wherein the adenosine A_(2a) receptor antagonist is represented by thestructural formula I

or a pharmaceutically acceptable salt thereof, wherein R is R¹-furanyl,R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide, R¹-oxazolyl, R¹⁰-phenyl,R¹-pyrrolyl or C₄-C₆ cycloalkenyl; X is C₂-C₆ alkylene or —C(O)CH₂—; Yis —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—, —(CH₂)₂—NH—, or

and Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl,diphenylmethyl, R⁶—C(O)—, R⁶—SO₂—, R⁶—OC(O)—, R⁷—N(R⁸)—C(O)—,R⁷—N(R⁸)—C(S)—,

 phenyl-CH(OH)—, or phenyl-C(═NOR²)—; or when Q is

Z is also phenylamino or pyridylamino; or Z and Y together are

R¹ is 1 to 3 substituents independently selected from hydrogen,C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, and C₁-C₆ alkylsulfonyl; R² and R³ areindependently selected from the group consisting of hydrogen and C₁-C₆alkyl; m and n are independently 2-3; Q is

R⁴ is 1-2 substituents independently selected from the group consistingof hydrogen and C₁-C₆alkyl, or two R⁴ substituents on the same carboncan form ═O; R⁵ is 1 to 5 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆alkoxy, —CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂,hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy,di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy,(C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy,di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy,(C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

 or adjacent R⁵ substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—,—O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to whichthey are attached; R⁶ is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl,thienyl, pyridyl, (C₃-C₆)-cycloalkyl,(C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl, or

R⁷ is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl; R⁸ is hydrogenor C₁-C₆ alkyl; or R⁷ and R⁸ together are —(CH₂)_(p)-A-(CH₂)_(q),wherein p and q are independently 2 or 3 and A is a bond, —CH₂—, —S— or—O—, and form a ring with the nitrogen to which they are attached; R⁹ is1-2 groups independently selected from hydrogen, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, halogen, —CF₃ and (C₁-C₆)alkoxy(C₁-C₆)alkoxy; R¹⁰ is 1 to5 substituents independently selected from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —CN, —NH₂,C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃ and—S(O)₀₋₂(C₁-C₆)alkyl; R¹¹ is H, C₁-C₆ alkyl, phenyl, benzyl, C₂-C₆alkenyl, C₁-C₆ alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl; R¹² is H or C₁-C₆alkyl; and R¹³ is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.
 16. Thecomposition of claim 15 wherein the adenosine A_(2a) receptor antagonistis represented by the formula

wherein R and Z-Y are as defined in the following table: Z—Y— R


17. A kit comprising in a single package, one container comprising anadenosine A_(2a) receptor antagonist in a pharmaceutically acceptablecarrier, and a separate container comprising an antidepressant inpharmaceutically acceptable carrier or an anxiolytic in apharmaceutically acceptable carrier, with the adenosine A_(2a) receptorantagonist and the antidepressant or anxiolytic agent being present inamounts such that the combination is effective to treat depression oranxiety-related disorders.